JP2012518004A - Process for producing phenyl-6- (1- (phenyl) ureido) nicotinamide - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds useful as inhibitors of p38 kinase. The process of the present invention facilitates large scale preparation of stable phenyl-6- (1- (phenyl) ureido) nicotinamide, which is produced in high purity and yield. The above process is faster for the desired product relative to the previous pathway by reducing the reaction time required to complete the individual transformations and by eliminating the need for further purification steps. Provides a simple generation.

Description

(Cross-reference to related applications)
This application claims priority to US Provisional Application No. 61 / 152,653, filed February 13, 2009. The entire contents of US Provisional Application No. 61 / 152,653 are incorporated herein in their entirety.

(Technical field of the invention)
The present invention relates to a process for the preparation of compounds useful as inhibitors of p38 kinase. The process of the present invention facilitates large scale preparation of stable phenyl-6- (1- (phenyl) ureido) nicotinamide, which is produced in high purity and yield.

(Background of the Invention)
Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen activated protein kinases (MAPKs) has been discovered. Members of this family are Ser / Thr kinases that activate their substrates by phosphorylation [1]. MAPKs are themselves activated by various signals, including growth factors, cytokines, UV radiation, and stress inducers.

  One particularly interesting MAPK is p38. p38 (also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK) is transfected with CD14, a lipopolysaccharide (LPS) receptor, and induced by LPS. Isolated from mouse pre-B cells. p38 has cDNA encoding it in humans and mice and was subsequently isolated and sequenced. Activation of p38 has been observed in cells stimulated by stress (eg, lipopolysaccharide (LPS), UV, anisomycin, or osmotic shock) and by cytokines (eg, IL-1 and TNF).

  Inhibition of p38 kinase results in a block against the production of both IL-1β and TNFα. IL-1 and TNF stimulate the production of other pro-inflammatory cytokines (eg, IL-6 and IL-8) and have been implicated in acute and chronic inflammatory diseases, as well as postmenopausal osteoporosis [2] ].

  Based on this finding, p38, along with other MAPKs, mediates cellular responses to inflammatory stimuli such as leukocyte accumulation, macrophage / monocyte activation, tissue absorption, fever, acute phase response and neutropenia. Is considered to have a role in doing. Furthermore, MAPK (eg, p38) has been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, asthma, osteoporosis and neurodegenerative diseases. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with overproduction of IL-1, IL-6, IL-8 or TNF are shown in US Pat.

  2- (2,4-Difluorophenyl) -6- (1- (2,6 difluorophenyl) ureido) nicotinamide (Compound I) having the structure shown below is useful for various diseases (acute and chronic inflammatory Efficacy for treatment of diseases (including disease) was demonstrated. Compound I is described in Patent Document 2 (08/26/2004 publication).

International Publication No. 96/21654 International Publication No. 2004/72038

B. Stein et al., Ann. Rep. Med. Chem. 1996, 31, 289-98. R. B. Kimble et al., Endocrinol. 1995, 136, 3054-61.

(Summary of the Invention)
As described herein, the present invention provides a process for preparing p38 kinase inhibitors that are useful in the treatment of many diseases, including acute and chronic inflammatory diseases. Such compounds include 2- (2,4-difluorophenyl) -6- (1- (2,6 difluorophenyl) ureido) nicotinamide (formula I) having the structure shown below.

The process of the invention has the advantage of allowing the preparation of stable compounds of formula 1 in high yield and purity, where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are It is defined below. The present invention has the further advantage of easy reaction conditions that are easily scaled up for large scale preparations. In addition, the above process reduces the reaction time required to complete individual conversions and eliminates the need for further purification steps, thereby reducing the desired product to the previous pathway. Provide faster generation.

(Detailed description of the invention)
(Detailed description of embodiment)
In one aspect, the present invention provides a compound of formula 4:

を調製するためのプロセスに関し、上記プロセスは、
式２の化合物：

With respect to the process for preparing
Compound of formula 2:

と、式３の化合物：

And a compound of formula 3:

とを、極性非プロトン化溶媒の存在下でカップリングする工程を包含する。

And in the presence of a polar aprotic solvent.

Each R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR Independent of 'CO ₂ R', NR'C (O) NR ' ₂ , OC (O) NR' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ R ', OC (O) R' Selected.

Each R ′ is independently of hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with 1 to 3 substituents. Selected, the substituents are independently selected from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic.

Each R ₃ is selected from hydrogen, C _1-6 aliphatic, and aryl, wherein the aryl is C _1-6 aliphatic, aryl, nitro, CN, CO ₂ R ′, CO ₂ N (R ′) ₂ , Optionally substituted with OR ′, NCO ₂ R ′, NR′C (O) N (R ′) ₂ , or OC (O) N (R ′) ₂ .

  Each X is independently a leaving group.

Each Z is independently selected from C _1-6 aliphatic, benzyl, Fmoc, or —SO ₂ R ′.

In one embodiment of this aspect, the solvent is dimethyl sulfoxide (DMSO), an N- methyl pyrrolidone (NMP), _CH 3 CN or dimethylformamide (DMF).

  In another embodiment, the solvent is DMSO.

  In one embodiment of this aspect, the coupling of the compound of formula 2 and the compound of formula 3 is performed in the presence of a base.

  In one embodiment of this aspect, the base is a metal carbonate or metal phosphate.

  In certain embodiments, the base is a metal carbonate (eg, cesium carbonate or potassium carbonate).

  In some specific embodiments, the base is cesium carbonate.

  In other embodiments, the base is a metal phosphate (eg, potassium phosphate).

  In one embodiment of this aspect, the coupling of the compound of formula 2 and the compound of formula 3 is performed at a temperature range of about 55-75 ° C. In another embodiment of this aspect, the coupling of the compound of formula 2 and the compound of formula 3 is performed at a temperature range of about 50-65 ° C. In yet a further embodiment of this aspect, the coupling of the compound of formula 2 and the compound of formula 3 is performed at a temperature range of about 55-60 ° C.

  In another aspect, the invention provides a compound of formula 5:

を調製するためのプロセスを提供し、上記プロセスは、
式４の化合物：

Provides a process for preparing the above process,
Compound of formula 4:

に対して、プロトン酸を使用して加水分解を行う工程を包含し、ここで
Ｒ_１、Ｒ_２、Ｒ_４、Ｒ_５、Ｒ’、Ｒ_３およびＺは、上記で定義される。

In contrast, the step of hydrolysis using a protonic acid is included, wherein R ₁ , R ₂ , R ₄ , R ₅ , R ′, R ₃ and Z are defined above.

  In one embodiment of this aspect, the hydrolysis of the compound of formula 4 above is performed in the presence of a solvent.

  In one embodiment of this aspect, the solvent is water.

In one embodiment of this aspect, the protic acid is sulfuric acid, HCl or H ₃ PO ₄ .

  In certain embodiments, the protic acid is sulfuric acid.

  In one embodiment of this aspect, the final concentration of sulfuric acid is about 7M.

  In one embodiment of this aspect, hydrolysis of the compound of Formula 4 above is performed at a temperature range of about 60-105 ° C.

  In certain embodiments, hydrolysis of the compound of Formula 4 above is performed at a temperature range of about 95-105 ° C.

  In a specific aspect, the hydrolysis of the compound of formula 4 above is performed at a temperature of about 100 ° C.

  In one embodiment of this aspect, hydrolysis of the compound of Formula 4 above is performed using a one-pot reaction.

  In another aspect, the invention provides a compound of formula 5:

を調製するためのプロセスを提供し、上記プロセスは、
式２の化合物：

Provides a process for preparing the above process,
Compound of formula 2:

に対して加水分解を行って、式１２の化合物：

Hydrolysis of the compound of formula 12:

を提供する工程；および
式１２の化合物と、式１１の化合物：

And a compound of formula 12 and a compound of formula 11:

とをカップリングする工程を包含し、ここで
Ｒ_１、Ｒ_２、Ｒ_４、Ｒ_５、Ｒ’、Ｒ_３およびＸは、上記に定義される。

Wherein R ₁ , R ₂ , R ₄ , R ₅ , R ′, R ₃ and X are defined above.

  In some embodiments of this aspect, the coupling step is performed in the presence of a solvent.

  In some further embodiments, the solvent can be selected from MTBE, THF, DMSO, MeTHF, toluene, pyridine, DMF, dichloromethane, diethyl ether, and ethyl acetate.

  In some embodiments of this aspect, the coupling step is performed in the presence of a base.

  In other embodiments, the base used in the coupling step can be selected from LiHMDS, NaHMDS, KHMDS, KOtBu, and nBuLi.

  In some embodiments, the base used in the coupling step is KHMDS.

  In some embodiments, the coupling reaction is performed at a temperature in the range of about −20 ° C. to 25 ° C. (eg, −20 ° C. to −10 ° C., −10 ° C. to −8 ° C., −10 ° C. to 0 ° C., or 0 ° C. to 25 ° C.).

  In another aspect, the invention provides a compound of formula 1:

を調製するためのプロセスを提供し、該プロセスは、
式５の化合物：

Providing a process for preparing
Compound of formula 5:

を、以下：
ｉ）尿素形成試薬；
ｉｉ）アミド化試薬；および
ｉｉｉ）無水アンモニア
で処理することによって、式５の化合物に対してアミド化もしくは尿素形成を行う工程、
を包含し、ここで
各Ｒ_１、Ｒ_２、Ｒ_４およびＲ_５は、水素、脂肪族、必要に応じて置換されたアリール、ニトロ、ＣＮ、ＯＲ’、ＣＯ_２Ｒ’、ＣＯ_２Ｎ（Ｒ’）_２、ＮＲ’ＣＯ_２Ｒ’、ＮＲ’Ｃ（Ｏ）ＮＲ’_２、ＯＣ（Ｏ）ＮＲ’_２、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＴｓ、ＯＭｓ、ＯＳＯ_２Ｒ’、ＯＣ（Ｏ）Ｒ’から独立して選択され；そして
各Ｒ’は、水素、Ｃ_１−６脂肪族、または１〜３個の置換基で必要に応じて置換された５〜６員の炭素環式環系もしくは複素環式環系から独立して選択され、該置換基はハロ、Ｃ_１−６アルコキシ、シアノ、ニトロ、アミノ、ヒドロキシ、およびＣ_１−６脂肪族から独立して選択される。

The following:
i) a urea-forming reagent;
ii) an amidation reagent; and iii) subjecting the compound of formula 5 to amidation or urea formation by treatment with anhydrous ammonia;
Wherein each R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ′, CO ₂ R ′, CO ₂ N ( R ′) ₂ , NR′CO ₂ R ′, NR′C (O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ R ′, OC (O ) R ′ independently selected; and each R ′ is hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic ring optionally substituted with 1 to 3 substituents Independently selected from a system or heterocyclic ring system, the substituents are independently selected from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic.

  In one embodiment of this aspect, the amidating reagent is phosgene, triphosgene or diphosgene.

  In one embodiment of this aspect, the urea-forming reagent is phosgene, triphosgene or diphosgene.

  In one embodiment of this aspect, the amidation reagent and urea-forming reagent are added simultaneously.

  In one embodiment of this aspect, the amidation reagent and urea-forming reagent are the same.

  In one embodiment of this aspect, the amidation and urea formation performed on the compound of Formula 5 is performed in the presence of a base.

  In one embodiment of this aspect, the base is diisopropylethylamine, Hunig base, or triethylamine.

  In certain embodiments, the base is diisopropylethylamine.

  In one embodiment of this aspect, the amidation and urea formation performed on the compound of Formula 5 is performed in the presence of a solvent.

  In one embodiment of this aspect, the solvent is THF, MeTHF, or toluene.

  In certain embodiments, the solvent is THF.

  In one embodiment of this aspect, the compound of formula 5 is treated with anhydrous ammonia after treatment with the amidation / urea forming reagent.

  In one embodiment of this aspect, anhydrous ammonia is added to the product obtained after treatment of the compound of formula 5 with the amidation / urea forming reagent without isolating the product.

  In one embodiment of this aspect, the process comprises treating the solution with anhydrous ammonia and then isolating the solid material, washing the solid material with water followed by an acid wash to form a compound of formula 1 The process of obtaining is further included.

In certain embodiments, the acid wash comprises a 1N H ₂ SO ₄ wash of the solid material.

  In another aspect, the present invention provides a process for providing a stable solid form of a compound of formula 1, wherein the process comprises a compound of formula 1:

の固体形態をスラリーにする工程を包含し、ここで
各Ｒ_１、Ｒ_２、Ｒ_４およびＲ_５は、水素、脂肪族、必要に応じて置換されたアリール、ニトロ、ＣＮ、ＯＲ’、ＣＯ_２Ｒ’、ＣＯ_２Ｎ（Ｒ’）_２、ＮＲ’ＣＯ_２Ｒ’、ＮＲ’Ｃ（Ｏ）ＮＲ’_２、ＯＣ（Ｏ）ＮＲ’_２、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＴｓ、ＯＭｓ、ＯＳＯ_２Ｒ’、ＯＣ（Ｏ）Ｒ’から独立して選択され；そして
各Ｒ’は、水素、Ｃ_１−６脂肪族、または１〜３個の置換基で必要に応じて置換された５〜６員の炭素環式環系もしくは複素環式環系から独立して選択され、該置換基はハロ、Ｃ_１−６アルコキシ、シアノ、ニトロ、アミノ、ヒドロキシ、およびＣ_１−６脂肪族から独立して選択される。

Each of R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR′CO ₂ R ′, NR′C (O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Br, I, OTs, OMs, Independently selected from OSO ₂ R ′, OC (O) R ′; and each R ′ is optionally substituted with hydrogen, C _1-6 aliphatic, or 1-3 substituents. Independently selected from a 6-membered carbocyclic or heterocyclic ring system, wherein the substituent is from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic Independently selected.

  In one embodiment of this aspect, the compound of Formula 1 above is stirred in a homogeneous or heterogeneous solvent system.

  In one embodiment of this aspect, the solvent system includes methanol and water.

  In one embodiment of this aspect, the methanol: water ratio in the solvent system is about 1: 3.

  In one embodiment of this aspect, the methanol: water ratio in the solvent system is about 1: 1.

  In one embodiment of this aspect, the compound is agitated for at least about 20 hours (eg, about 24 hours).

  In one embodiment of this aspect, the compound is stirred in a solvent system having a methanol: water ratio of about 1: 3 for at least about 20 hours (eg, about 24 hours) and then at least about 20 hours ( For example, in a solvent system having a methanol: water ratio of about 1: 1 for about 24 hours).

In one embodiment of the invention, each R ₁ , R ₂ , R ₄ and R ₅ is independently selected from hydrogen, F, Cl, Br, I, OTs or OMs.

In a further embodiment, each R ₁ , R ₂ , R ₄ and R ₅ is independently selected from hydrogen or F.

In one embodiment of the invention, each R ₃ is independently selected from hydrogen or C _1-6 aliphatic.

In a further embodiment, each R ₃ is independently selected from hydrogen or ethyl.

In one embodiment of the invention, each Z is independently C _1-6 aliphatic.

  In a further embodiment, each Z is independently tert-butyl.

  In another aspect, the invention provides compound 10:

を調製するためのプロセスを提供し、上記プロセスは、化合物１１：

Provides a process for the preparation of compound 11:

と、化合物６：

And compound 6:

をメチルｔｅｒｔ−ブチルエーテル（ＭＴＢＥ）中で溶解させ、上記混合物を、塩基で処理し、上記混合物を、約−８℃〜−１０℃の温度で攪拌することによって化合物１１と化合物６をカップリングして、化合物９：

Is dissolved in methyl tert-butyl ether (MTBE), the mixture is treated with a base, and the mixture is stirred at a temperature of about −8 ° C. to −10 ° C. to couple compound 11 and compound 6. Compound 9:

を得る工程；
化合物９を、トリホスゲンおよびジイソプロピルエチルアミンで、テトラヒドロフランの存在下で処理する工程；ならびに
上記溶液を、上記反応が完了するまで攪拌する工程；ならびに
上記溶液を無水アンモニアで処理する工程を包含する。

Obtaining
Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran; and stirring the solution until the reaction is complete; and treating the solution with anhydrous ammonia.

  In one embodiment of this aspect, the base is LiHMDS, NaHMDS, KHMDS, KOtBu, or nBuLi.

  In a further embodiment, the base is KHMDS.

  In further embodiments, the reaction temperature is between about -20 ° C and 25 ° C (eg, -20 ° C to -10 ° C, -10 ° C to -8 ° C, -10 ° C to 0 ° C, or 0 ° C to 25 ° C. ).

  In one embodiment of this aspect, the process comprises treating the solution with anhydrous ammonia followed by isolating the solid material, and washing the solid material with water followed by an acid wash to provide compound 10 The process of obtaining is further included.

In certain embodiments, the acid wash comprises a 1N H ₂ SO ₄ wash of the solid material.

  In another embodiment, the reaction temperature is about 55 ° C. In a further aspect, the present invention provides a compound of formula 5:

を調製するためのプロセスを提供し、該プロセスは、
式７の化合物：

Providing a process for preparing
Compound of formula 7:

に対して、プロトン酸を使用して加水分解する工程を包含し、ここで
Ｒ_１、Ｒ_２、Ｒ_４、Ｒ_５、Ｒ’およびＲ_３は、上記で定義される。

For R ₁ , R ₂ , R ₄ , R ₅ , R ′ and R ₃ are defined above.

  In one embodiment of this aspect, the compound 11 is hydrolyzed in the presence of a solvent.

  In one embodiment of this aspect, the solvent is water.

  In one embodiment of this aspect, the protonic acid is sulfuric acid.

  In one embodiment of this aspect, the final concentration of sulfuric acid is about 7M.

  In another aspect, the invention provides compound 10:

を調製するためのプロセスを提供し、上記プロセスは、
化合物５：

Provides a process for preparing the above process,
Compound 5:

と、化合物７：

And compound 7:

をジメチルスルホキシド中に溶解させ、上記混合物を炭酸セシウムで処理し、上記混合物を、約５０〜６５℃の温度（例えば、５５〜６０℃）で攪拌することによって化合物５と化合物７をカップリングして、化合物８：

Is dissolved in dimethyl sulfoxide, the mixture is treated with cesium carbonate, and the mixture is stirred at a temperature of about 50-65 ° C. (eg, 55-60 ° C.) to couple compound 5 and compound 7. Compound 8:

を得る工程；
化合物８を、約７Ｍ硫酸の水溶液で処理する工程、および
上記混合物を、約９５〜１０５℃の温度（例えば、１００℃）で攪拌して、化合物９：

Obtaining
Treating Compound 8 with an aqueous solution of about 7 M sulfuric acid, and stirring the mixture at a temperature of about 95-105 ° C. (eg, 100 ° C.) to form Compound 9:

を得る工程、
化合物９を、テトラヒドロフランの存在下で、トリホスゲンおよびジイソプロピルエチルアミンで処理する工程；
上記溶液を、上記反応が完了するまで攪拌する工程；ならびに
上記溶液を、無水アンモニアで処理する工程
を包含する。

Obtaining a step,
Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran;
Stirring the solution until the reaction is complete; and treating the solution with anhydrous ammonia.

  In one embodiment of this aspect, the process comprises isolating solid material after treating the solution with anhydrous ammonia, and washing the solid material with water followed by acidification to provide compound 10 The process of obtaining is further included.

In certain embodiments, the acid wash comprises a 1N H ₂ SO ₄ wash of the solid material.

  In some further embodiments, the process is agitating compound 10 in a solvent system comprising methanol and water, wherein the methanol: water ratio is at least about 20 hours (eg, about Over about 24 hours); adding methanol to the mixture to change the solvent ratio to about 1: 1 methanol: water; and over at least about 20 hours (eg, about 24 hours) Including the step of continuing to stir.

  In one aspect, the invention includes a compound produced by the process of any of the above embodiments.

  In one aspect, the present invention provides a pharmaceutical composition produced by the process of any of the above embodiments.

(Definitions and general terms)
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75 th Ed). In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic ^Chemistry", 5 th Ed. Ed. Smith, M .; B. and March, J.A. , John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

  As described herein, compounds of the present invention may include one or more substituents (eg, generally exemplified above or exemplified by certain classes, subclasses, and species of the present invention). ) Can be optionally substituted. It is recognized that the phrase “substituted as needed” is used interchangeably with the phrase “substituted or not substituted”. In general, the term “substituted” refers to substituting a radical of a specified substituent for a hydrogen radical in a given structure, whether or not preceded by the term “optional”. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable portion of the group, with more than one position in any given structure selected from a particular group Where more than one substituent may be substituted, the substituents may be the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the form of stable or chemically feasible compounds. The term “stable” as used herein for their production, detection, and preferably their recovery, purification, and one or more of the purposes disclosed herein. When subjected to conditions that allow its use, it refers to a compound that is not substantially added. In some embodiments, the stable or chemically feasible compound is maintained at a temperature of 40 ° C. or lower for at least 1 week in the absence of moisture or other chemically reactive conditions. In this case, there is substantially no change.

The term “aliphatic” or “aliphatic group” as used herein is linear (ie, unbranched) that is fully saturated or contains one or more unsaturated units. ) Or branched, substituted or unsubstituted hydrocarbon chains, or fully saturated or containing one or more unsaturated units, but one point of attachment to the rest of the molecule Means a non-aromatic monocyclic or bicyclic hydrocarbon (referred to herein as “carbocyclic”, “cycloaliphatic” or “cycloalkyl”) having Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) is fully saturated or contains one or more unsaturated units, but is not aromatic, A monocyclic C ₃ -C ₈ hydrocarbon or a bicyclic or tricyclic C ₈ -C ₁₄ hydrocarbon, wherein any individual ring of the bicyclic ring system has 3 to 7 members One having one point of attachment to the rest of the molecule it has. Suitable aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof (eg, (cycloalkyl) alkyl, (cycloalkenyl). ) Alkyl or (cycloalkyl) alkenyl)), but is not limited thereto. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (eg, decalin), bridged bicycloalkyl (eg, norbornyl or [2.2.2] bicyclo-octyl), or bridged tricyclic (eg, And adamantyl).

  The term “heteroaliphatic”, as used herein, has one or two carbon atoms replaced independently by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Means an aliphatic group. The heteroaliphatic group may be substituted or unsubstituted, may be branched, unbranched, or cyclic. May be acyclic and includes “heterocyclic”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” groups.

  The terms “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” as used herein, are non-aromatic, monocyclic, bicyclic, or tricyclic. A ring system of the formula, wherein one or more ring members are independently selected heteroatoms. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group is such that one or more ring members are independent of oxygen, sulfur, nitrogen, or phosphorus. And each ring in the above system has 3 to 14 ring members, including 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon); any quaternized form of any basic nitrogen; or heterocyclic Of the ring substitutable nitrogen (eg, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)) Means one or more.

  The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

  The term “alkoxy”, or “thioalkyl”, as used herein, is the main carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom, as defined above. Refers to an alkyl group attached to.

The terms “haloaliphatic” and “haloalkoxy” mean an aliphatic or alkoxy optionally substituted with one or more halo atoms. The term “halogen” or “halo” means F, Cl, Br, or I. Examples of haloaliphatic include —CHF ₂ , —CH ₂ F, —CF ₃ , —CF ₂ —, or perhaloalkyl (eg, —CF ₂ CF ₃ ).

  The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to a monocyclic ring having a total of 5-14 ring members Formula, bicyclic, and tricyclic ring systems, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members Say. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to a heteroaryl ring system, as defined below.

  The term “heteroaryl” used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic, having a total of 5 to 14 ring members And at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and in this system Each ring contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group can contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include ^{halo; -R o; -OR o; -SR} o; 1,2- methylene - dioxy; 1,2-ethylenedioxy; R phenyl optionally substituted with ^o (Ph); ^{R o} -O that is optionally substituted with (Ph); optionally substituted with _{^{R o - (CH 2) 1-2}} (Ph ); ^{R o} is optionally substituted with a _{^{-CH = CH (Ph); -}} NO 2; -CN; -N (R o) 2; -NR o C (O) R o; -NR o C ( _{^{O) N (R o) 2}} ; -NR o CO 2 R o; -NR o NR o C (O) R o; -NR o NR o C (O) N (R o) 2; -NR o NR o _{^{CO 2 R o; -C (O}} ) C (O) R o; -C (O) CH 2 C (O) R o; -CO 2 R o; - _{^{(O) R o; -C (}} O) N (R o) 2; -OC (O) N (R o) 2; -S (O) 2 R o; -SO 2 N (R o) 2; - _{^{S (O) R o; -NR}} o SO 2 N (R o) 2; -NR o SO 2 R o; -C (= S) N (R o) 2; -C (= NH) -N (R ^o ) ₂ ; or — (CH ₂ ) _0-2 NHC (O) R ^o, where each independent ^occurrence of R ^o is hydrogen, optionally substituted C _1-6 aliphatic, substituted Not selected from 5 to 6 membered heteroaryl or heterocyclic ring, phenyl, —O (Ph), or —CH ₂ (Ph), or the same or different substituents, regardless of the above definition two independent occurrences of the above R ^o, taken together with the atoms to which each R ^o group is bound, 3-8 membered cycloalkyl, f Roshikuriru, aryl or nitrogen, oxygen, or form a heteroaryl ring having 0-3 heteroatoms independently selected from sulfur. Choices substituents on the aliphatic group of the R ^o, is NH _2, NH _{(C 1-4} aliphatic), _{N (C 1-4 aliphatic) 2, halo, C 1-4} aliphatic, OH, _{O (C 1-4 aliphatic),} NO 2, CN, _{CO 2 H, CO 2 (C} 1-4 aliphatic), O (halo _{C 1-4} aliphatic), or is selected from halo _{C 1-4} aliphatic, wherein _{C 1-4} fat foregoing ^{R o} Each of the group groups is not substituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic group, or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of the aryl or heteroaryl group, and these the include the _{following: = O, = S, =} NNHR *, = NN (R *) 2, = NNHC (O) R *, = NNHCO 2 ( alkyl), = NNHSO ₂ (alkyl), or = NR * Where each R * is independently selected from hydrogen or optionally substituted C _1-6 aliphatic. Choice substituents on the aliphatic group of R * _are, NH 2, NH _{(C 1-4} aliphatic), _{N (C 1-4 aliphatic) 2, halo, C 1-4} aliphatic, OH , O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic), or halo (C _1-4 fat) Group) (wherein each of the aforementioned _C1-4 aliphatic groups of R * is unsubstituted).

Choice substituents on the nitrogen of a heterocyclic ring of _{^{non-aromatic, -R +, -N (R +}} ) 2, -C (O) R +, -CO 2 R +, -C (O) _{^{C (O) R +, -C}} (O) CH 2 C (O) R +, -SO 2 R +, -SO 2 N (R +) 2, -C (= S) N (R +) 2, ^{-C (= NH) -N (R} +) 2, or ^-NR + _sO 2 ^{R +} (where ^{R +} is hydrogen, _{C 1-6} aliphatic optionally substituted, optionally substituted Phenyl optionally substituted —O (Ph), optionally substituted —CH ₂ (Ph), optionally substituted — (CH ₂ ) _1-2 (Ph) Optionally substituted —CH═CH (Ph); or substituted having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. Is selected from 5-6 membered heteroaryl or heterocyclic ring does not, or regardless of the definition above, two independent occurrences of R ⁺ on the same substituent or different substituents, each A heterocycle having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, together with the atoms to which the R ⁺ group is attached, 3-8 membered cycloalkyl, heterocyclyl, aryl, or An aryl ring is formed. The optionally substituted substituents on the R ⁺ aliphatic group or the phenyl ring are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halo, C _1-4 aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic), Or selected from halo (C _1-4 aliphatic), wherein each of the aforementioned C _1-4 aliphatic groups for R ⁺ is unsubstituted.

  The term “alkylidene chain” may be fully saturated, may have one or more units of unsaturation, and has two points of attachment in the rest of the molecule, linear or Reference is made to branched carbon chains. The term “spirocycloalkylidene” may be fully saturated or may have one or more unsaturated units, and refers to two points of attachment from the same ring carbon atom to the rest of the molecule. Reference is made to a carbocyclic ring having.

  The term “stable” as used herein for their purification, detection, and preferably one or more of their recovery, purification, and purposes disclosed herein. Is a compound that does not substantially change when subjected to conditions that allow its use (eg, administration to a mammal by methods known in the art). In some embodiments, the stable or chemically feasible compound is maintained at a temperature of 40 ° C. or lower for at least 1 week in the absence of moisture or other chemically reactive conditions. In this case, there is substantially no change.

The term “leaving group” as used herein refers to “March's Advanced Organic Chemistry”, 5 ^th Ed. Ed. Smith, M .; B. and March, J.A. , John Wiley & Sons, New York: 2001.

The term “amidation” as used herein is defined as a process for generating an amide moiety. An example of this type of process is, without limitation, coupling of an ammonia or amine functional group with a compound having a carbonyl that itself has a leaving group. A depicted representative of a non-limiting general example of the process of amidation (where X is a leaving group and R ^o is defined above) is:

用語「尿素」とは、本明細書で使用される場合、２個のアミン官能基を有するカルボニルをその構造中に含む任意の化合物として定義される。尿素の非限定的一般例の描写されている代表（ここでＲ^ｏは上記のように定義される）は、以下である：

The term “urea” as used herein is defined as any compound containing in its structure a carbonyl having two amine functional groups. A depicted representative of a non-limiting general example of urea (where R ^o is defined as above) is:

用語「尿素形成試薬」とは、本明細書で使用される場合、カルボニル含有化合物であって、カルボニル部分が２個の脱離基を有するものとして定義され、以下に定義されるように、尿素形成のプロセスに関与し得る。

The term “urea-forming reagent” as used herein is a carbonyl-containing compound, where the carbonyl moiety is defined as having two leaving groups, and as defined below, urea Can be involved in the formation process.

The term “urea formation” as used herein is defined as a process for producing a urea moiety. An example of this type of process is, without limitation, coupling of an ammonia or amine functional group with a urea forming reagent. Depicted representatives of a non-limiting general example of the process of urea formation, where X ₁ and X ₂ are leaving groups and R ^o is defined above are as follows: :

用語「ワンポット反応」とは、本明細書で使用される場合、中間体化合物の分離も精製もなく、基質の２個以上の異なる化学的変換が、１種以上の試薬の段階的もしくは同時の添加の際に起こるプロセスとして定義される。

The term “one-pot reaction”, as used herein, refers to the stepwise or simultaneous conversion of two or more different chemical transformations of one or more reagents without the separation or purification of intermediate compounds. Defined as the process that occurs upon addition.

  The term “slurry” as used herein is defined as a mixture comprising a solid and a liquid, where the solid is at most partially soluble in the liquid. The terms “slurrying” or “slurried” as used herein (eg, “slurry the above solid product for 24 hours”) make a slurry and Defined as the act of stirring the slurry over time.

The term “protecting group” as used herein is a group intended to protect functional groups (eg, alcohols, amines, carboxyls, carbonyls, etc.) from unwanted reactions during synthetic procedures. Represents. Protecting groups which are commonly ^{used, Greene and Wuts, Protective Groups in} Organic Synthesis, 3 rd Edition (John Wiley & Sons, New York, 1999) ( which is herein incorporated by reference) disclosed . Examples of nitrogen protecting groups include acyl, aroyl, or carbamoyl groups (eg, formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-Nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliary substances (eg protected or unprotected D, L or D, L-amino acids (Eg, alanine, leucine, phenylalanine, etc.); sulfonyl groups (eg, benzenesulfonyl, p-toluenesulfonyl, etc.); carbamate groups (eg, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, -Methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxy Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, etho Sicarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenyl Thiocarbonyl etc.), arylalkyl groups (eg benzyl, triphenylmethyl, benzyloxymethyl etc.) and silyl groups (eg trimethylsilyl etc.) Preferred N-protecting groups are tert-butyloxycarbonyl (Boc) It is.

  Examples of useful protecting groups for acids are substituted alkyl esters (eg 9-fluorenylmethyl), methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxy Methyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol, phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, Rohekishiru, allyl, methallyl, cinnamyl (Cynnamyl), phenyl, silyl esters, benzyl and substituted benzyl esters, 2,6-dialkyl phenyl ester (e.g., pentafluorophenyl), a 2,6-dialkyl phenyl. Preferred protecting groups for acids are methyl esters or ethyl esters.

Methods for adding such amine and acid protecting groups (generally referred to as “protection”) and methods for removing (generally referred to as “deprotection”) are well known in the art, see, for example, P.I. J. et al. Kocienski, Protecting Groups, Thieme, 1994 ( which in its entirety is incorporated by reference herein) and ^{Greene and Wuts, Protective Groups in Organic} Synthesis, 3 rd Edition (John Wiley & Sons, New York, 1999) in Available.

Unless otherwise indicated, the structures shown herein are also meant to include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the above structures. For example, R and S configurations for each asymmetric center, (Z) double bond isomer and (E) double bond isomer, and (Z) conformer and (E) conformer body. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometrical mixtures (or conformational mixtures) of the present compounds are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Further, unless otherwise indicated, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, except that hydrogen is replaced with deuterium or tritium, or carbon is replaced with ¹³ C-enriched carbon or ¹⁴ C-enriched carbon are within the scope of the present invention. Is within. Such compounds are useful, for example, as analytical tools, probes in biological assays, or p38 inhibitors with improved therapeutic profiles.

(Processes and intermediates)
As used herein, abbreviations, symbols and conventions are consistent with those used in modern scientific literature. For example, Janet S. et al. Dodd, ed. The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed. , Washington, D .; C. : American Chemical Society, 1997 (incorporated herein by reference in its entirety).

  Compounds of formula 1 can be synthesized according to Scheme 1.

式８の化合物は、式６の化合物（ここでＸは脱離基である）と、ホウ酸、式７の化合物とを、適切な有機溶媒（例えば、ＥｔＯＨ）中で、適切な遷移金属触媒（例えば、パラジウムテトラキス（トリフェニルホスフィン））の存在下で、適切な塩基（例えば、アルカリ金属塩基（例えば、Ｎａ_２ＣＯ_３））の存在下で、７０℃〜９０℃の間の温度でカップリングすることによって、調製され得る。式６の化合物および式７の化合物は、商業的に購入され得るか、または当業者に公知の方法を使用して合成され得る。

The compound of formula 8 is a compound of formula 6 (where X is a leaving group) and boric acid, a compound of formula 7, in a suitable organic solvent (eg, EtOH) in a suitable transition metal catalyst. (e.g., palladium tetrakis (triphenylphosphine)) in the presence of a suitable base (e.g., alkali metal base _(e.g., Na 2 _CO 3)) in the presence of a cup at a temperature between 70 ° C. to 90 ° C. It can be prepared by ringing. Compounds of formula 6 and 7 can be purchased commercially or synthesized using methods known to those skilled in the art.

An N-oxide compound of formula 9 is obtained from a compound of formula 8 in a suitable solvent (eg, CH ₂ Cl ₂ ) at a suitable temperature (eg, 20-40 ° C.) and a suitable oxidizing agent (eg, mCPBA). Can be prepared by oxidation with.

A compound of formula 2 can be synthesized by treatment of a compound of formula 9 with a suitable agent (eg, chlorinating agent (eg, POCl ₃ ) in a suitable solvent (eg, 1,2-dichloroethane).

The compound of formula 4 is obtained by coupling the compound of formula 2 and the compound of formula 3 in the presence of a suitable alkali metal salt (eg cesium carbonate) and a suitable polar organic solvent (eg DMSO). Can be synthesized. The reaction mixture is then treated with a suitable dilute aqueous acid solution (eg, 1N HCl) and the product is recrystallized from a suitable polar solvent (eg, EtOH). Alternatively, the compound of formula 4 is as generally described in PCT application WO 2004/072038 and US Pat. No. 7,115,746, the disclosures of which are hereby incorporated by reference in their entirety. Can be prepared by coupling a compound of Formula 2 and a compound of Formula 3 in the presence of a transition metal catalyst (eg, Pd (OAc) ₂ ). Phenyl carbamates of formula 4 can be purchased commercially or synthesized from the corresponding aniline using methods known to those skilled in the art.

  A compound of formula 5 is prepared from a compound of formula 4 from a one-pot procedure where the compound of formula 4 is treated with an acid in such a way as to promote hydrolysis of the carbamate and ester functional groups. Can be done. Alternatively, a compound of formula 5 can be prepared from a compound of formula 4 by first hydrolyzing the carbamate group followed by hydrolysis of the ester to its corresponding carboxylic acid.

  A compound of formula 1 can be prepared from a compound of formula 5 by reacting the compound of formula 5 with triphosgene or a suitable permeable reagent, followed by treatment with anhydrous ammonia.

  The compound of formula 1 can also be recrystallized to a more stable form by treating the compound of formula 1 with a mixture of water and a polar protic organic solvent.

  The following preparative examples are presented so that the invention might be more fully understood. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention.

  (Example 1: Preparation of ethyl 6-chloro-2- (2,4-difluorophenyl) nicotinate (5))

（エチル ２−（２，４−ジフルオロフェニル）ニコチネート（３）の調製）

(Preparation of ethyl 2- (2,4-difluorophenyl) nicotinate (3))

オーバーヘッドスターラー、熱電対、加熱マントル、窒素出口および還流冷却器を備えた、窒素をパージした３．０Ｌの四つ口フラスコに、Ｐｄ（Ｐｈ_３）_４（５．０ｇ，４．３３ミリモル，０．００５当量）、炭酸ナトリウム（９２．６ｇ，８７４ミリモル，１．３当量）、エチル ２−クロロニコチネート １（１２６．０ｇ，６７８モル，１．０当量）、２，４−ジフルオロフェニルボロン酸 ２（１２５ｇ，７９１ミリモル，１．２当量）を充填し、続いて、０．５Ｌ トルエンおよび１２５ｍＬ 変性ＥｔＯＨを充填した。上記反応系を、８２℃へと、Ｎ_２下で一晩激しく攪拌しながら加熱した（反応の完了は、ＨＰＬＣおよびＴＬＣによって決定した）。上記反応系を、室温へと冷却し、上記混合物を、小さなセライト（登録商標）のパッドを通して濾過し、上記溶媒を、真空下で５５℃において除去した。その残渣を、ＥｔＯＡｃ中に溶解させ、洗浄し、乾燥させ（ＭｇＳＯ_４）、再びセライト^{（登録商標）}を通して濾過し、濃縮した。その生成物を、黄色固体として得た。

A nitrogen-purged 3.0 L four-necked flask equipped with an overhead stirrer, thermocouple, heating mantle, nitrogen outlet and reflux condenser was charged with Pd (Ph ₃ ) ₄ (5.0 g, 4.33 mmol, 0 0.005 equivalent), sodium carbonate (92.6 g, 874 mmol, 1.3 eq), ethyl 2-chloronicotinate 1 (126.0 g, 678 mol, 1.0 eq), 2,4-difluorophenylboronic acid 2 (125 g, 791 mmol, 1.2 eq) was charged followed by 0.5 L toluene and 125 mL modified EtOH. The reaction was heated to 82 ° C. with vigorous stirring overnight under N ₂ (reaction completion was determined by HPLC and TLC). The reaction was cooled to room temperature, the mixture was filtered through a small pad of Celite® and the solvent was removed at 55 ° C. under vacuum. The residue was dissolved in EtOAc, washed, dried (MgSO _4), filtered through ^{Celite (R)} again, and concentrated. The product was obtained as a yellow solid.

  (Preparation of 2- (2,4-difluorophenyl) -3- (ethoxycarbonyl) pyridine 1-oxide (4))

オーバーヘッドスターラー、熱電対および冷却器を備えた窒素でパージした、１２Ｌの五つ口フラスコに、エチル ２−（２，４−ジフルオロフェニル）ニコチネート ３（１４４ｇ，５４８ミリモル，１．０当量）、および４Ｌ ＣＨ_２Ｃｌ_２を充填した。攪拌しながら、ｍＣＰＢＡを５分間にわたって添加し、その温度を、２２℃から３８℃へと４５分かけて徐々に上昇させた（反応の完了は、ＨＰＬＣによって決定した）。上記反応系を室温へと冷却し、その内容物を、３Ｌの水の中にゆっくりと注いだ。ペルオキシド試験（デンプン／Ｉ_２紙）が、上記混合物中に残っているペルオキシドがないことを示すまで、Ｎａ_２ＳＯ_３をゆっくりと添加した（２０から３３℃への発熱）。その水層を分離し、その有機層を、飽和ＮａＨＣＯ_３（約３Ｌ）で洗浄した。上記有機層を、ＭｇＳＯ_４で乾燥させ、濾過し、褐色の粘稠性の油状物へと濃縮した。次いで、上記油状物を、ＭＴＢＥ（２Ｌ）で処理し、攪拌して、白色沈殿物を得、これを、濾過によって集め、ＭＴＢＥで洗浄し、真空下で乾燥させて、標題化合物４を得た。

In a 12 L five-necked flask purged with nitrogen equipped with an overhead stirrer, thermocouple and condenser, ethyl 2- (2,4-difluorophenyl) nicotinate 3 (144 g, 548 mmol, 1.0 equiv), and Charged with 4 L CH ₂ Cl ₂ . While stirring, mCPBA was added over 5 minutes and the temperature was gradually increased from 22 ° C. to 38 ° C. over 45 minutes (reaction completion was determined by HPLC). The reaction system was cooled to room temperature and the contents were slowly poured into 3 L of water. Na ₂ SO ₃ was added slowly (exotherm from 20 to 33 ° C.) until the peroxide test (starch / I ₂ paper) showed no peroxide remaining in the mixture. The aqueous layer was separated and the organic layer was washed with saturated NaHCO ₃ (about 3 L). The organic layer was dried over MgSO ₄ , filtered and concentrated to a brown viscous oil. The oil was then treated with MTBE (2 L) and stirred to give a white precipitate which was collected by filtration, washed with MTBE and dried under vacuum to give the title compound 4. .

  (Preparation of ethyl 6-chloro-2- (2,4-difluorophenyl) nicotinate (5))

還流冷却器、加熱マントルおよび熱電対を備えた、窒素でパージした５００ｍＬの三つ口フラスコに、２−（２，４−ジフルオロフェニル）−３−（エトキシカルボニル）ピリジン １−オキシド ４（２１ｇ，７５ミリモル，１．０当量）を添加し、続いて、１５０ｍＬ ジクロロエタンを添加した。オキシ塩化リン（７５ｍＬ）を、攪拌しながら一度に（ｉｎ ｏｎｅ ａｌｉｑｕａｔｅ）添加し、２１℃から２３℃へと温度を急激に上昇させ、続いて、徐々に加温した。上記溶液を、７０〜７５℃へと窒素下で加熱した（反応の完了を、ＨＰＬＣによって決定した）。次いで、上記反応系を、室温へと冷却し、真空下で濃縮して、上記ＰＯＣｌ_３の大部分を除去した。その残りを、４５０ｇの氷上へゆっくりと注ぐことによってクエンチした。次いで、上記混合物（氷が溶けた後）を、塩化メチレンへと抽出した（２×２００ｍＬ）。合わせた有機物を乾燥させ（ＭｇＳＯ_４）、シリカを通して濾過し、塩化メチレンで溶出し、濃縮して、標題化合物５を橙色固体として得た。^１Ｈ ＮＭＲ（５００．０ＭＨｚ，ＣＤＣｌ_３） ｄ ８．１５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）， ７．５４（ｔｄ，Ｊ＝８．５，５．０Ｈｚ，１Ｈ）， ７．３４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）， ６．９６−６．９２（ｍ，１Ｈ）， ６．７９−６．７４ （ｍ，１Ｈ）， ４．１６（ｑ，Ｊ＝７．２Ｈｚ，２ Ｈ）， １．１０（ｔ，Ｊ＝７．１Ｈｚ，Ｈ） ｐｐｍ。

A nitrogen purged 500 mL three neck flask equipped with a reflux condenser, heating mantle and thermocouple was charged with 2- (2,4-difluorophenyl) -3- (ethoxycarbonyl) pyridine 1-oxide 4 (21 g, 75 mmol, 1.0 eq.) Followed by 150 mL dichloroethane. Phosphorus oxychloride (75 mL) was added in one aliquot with stirring to raise the temperature rapidly from 21 ° C. to 23 ° C., followed by gradual warming. The solution was heated to 70-75 ° C. under nitrogen (reaction completion was determined by HPLC). The reaction was then cooled to room temperature and concentrated in vacuo to remove most of the POCl ₃ . The rest was quenched by slowly pouring onto 450 g of ice. The mixture (after the ice melted) was then extracted into methylene chloride (2 × 200 mL). The combined organics were dried (MgSO ₄ ), filtered through silica, eluted with methylene chloride and concentrated to give the title compound 5 as an orange solid. ¹ H NMR (500.0 MHz, CDCl ₃ ) d 8.15 (d, J = 8.2 Hz, 1H), 7.54 (td, J = 8.5, 5.0 Hz, 1H), 7.34 ( d, J = 8.2 Hz, 1H), 6.96-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.16 (q, J = 7.2 Hz, 2) H), 1.10 (t, J = 7.1 Hz, H) ppm.

  (Example 2: Preparation of tert-butyl 2,6-difluorophenylcarbamate (7))

２，６−ジフルオロアニリン ６（４．５ｍＬ，４２ｍｍｏｌ，１．０当量）、およびＢｏｃ無水物（１１．１ｇ，５１ｍｍｏｌ，１．２当量）を、ＴＨＦ中に混合し、この混合物に、１Ｍ ナトリウムヘキサメチルジシラジド（ｈｅｘａｍｅｔｈｙｌｄｉｓｉｌａｚｉｄｅ）（１００ｍＬ，１００ｍｍｏｌ，２．３当量）を室温において添加した（反応の完了を、ＨＰＬＣによって決定した）。次いで、５０ｍＬ ブラインを添加し、上記溶液を濃縮し、ＥｔＯＡｃ（２×１００ｍＬ）で抽出した。その合わせた有機物をブライン（１×５０ｍＬ）で洗浄し、続いて、クエン酸（２×１０％）で洗浄した。次いで、その得られた溶液をＭｇＳＯ_４で乾燥させ、濾過し、濃縮して、標題化合物７を橙色固体として得た。これを、さらに精製せずに次の工程で直接使用した。^１Ｈ ＮＭＲ（５００．０ＭＨｚ，ＣＤＣｌ３） ７．１８−７．１３（ｍ，１Ｈ）， ６．９６−６．９１（ｍ，２Ｈ）， ６．０６（ｓ，１Ｈ）および１．５２（ｓ，９Ｈ） ｐｐｍ。

2,6-Difluoroaniline 6 (4.5 mL, 42 mmol, 1.0 eq), and Boc anhydride (11.1 g, 51 mmol, 1.2 eq) were mixed in THF and to this mixture was added 1M sodium salt. Hexamethyldisilazide (100 mL, 100 mmol, 2.3 eq) was added at room temperature (completion of the reaction was determined by HPLC). 50 mL brine was then added and the solution was concentrated and extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine (1 × 50 mL) followed by citric acid (2 × 10%). The resulting solution was then dried over MgSO ₄ , filtered and concentrated to give the title compound 7 as an orange solid. This was used directly in the next step without further purification. ¹ H NMR (500.0 MHz, CDCl 3) 7.18-7.13 (m, 1H), 6.96-6.91 (m, 2H), 6.06 (s, 1H) and 1.52 (s , 9H) ppm.

  Example 3: Preparation of ethyl 6- (tert-butoxycarbonyl (2,6-difluorophenyl) amino) -2- (2,4-difluorophenyl) nicotinate (8)

化合物５（１００．８２ｇ，０．３３ｍｏｌ，１．０当量）、化合物７（１０１．０５ｇ，０．４４ｍｏｌ，１．３０当量）、および炭酸セシウム（１７７．１２ｇ，０．５４ｍｏｌ，１．６０当量）の混合物を、ＤＭＳＯ（２５０ｍＬ，２．５容積）中に懸濁し、５５〜６０℃で４８時間にわたって激しく攪拌した（反応の完了を、ＨＰＬＣによって決定した）。上記混合物を、２０〜３０℃へと冷却し、上記塩基を、上記反応混合物の内部温度を３０℃未満に維持して、１Ｎ ＨＣｌ（水）溶液（５４０ｍＬ，１．６０当量）を注意深くかつゆっくりと添加することによってクエンチした。冷却の際に、沈殿物が形成し、これを濾過し、水（２×２５０ｍＬ、２×２．５容積）で洗浄した。次いで、上記沈殿物を、無水エタノール（１０００ｍＬ，１０容積）中に懸濁し、還流するまで加熱した。上記還流を３０〜６０分間維持し、水（２００ｍＬ，２容積）を、上記混合物に添加した。次いで、上記得られた混合物を、再び還流するまで加熱し、還流を３０分間にわたって維持し、その時点で、上記懸濁物を、１０℃へと冷却した。次いで、その得られた固体を濾過し、水（２×２５０ｍＬ，２×２．５容積）で洗浄し、続いて、無水エタノール（２５０ｍＬ，２．５容積）で洗浄し、次いで、真空オーブンへと移し、５０〜６０℃において乾燥させた。標題化合物８を、白色結晶性固体として得た。（^１Ｈ ＮＭＲ，５００ＭＨｚ；ＣＤＣｌ_３） δ ８．２８（ｄ，１Ｈ）， ８．１２（ｄ，１Ｈ）， ７．１９（ｑ，１Ｈ）， ６．９６（ｔ，２Ｈ）， ６．８１（ｔ，１Ｈ）， ６．７４（ｔ，１Ｈ）， ４．２５（ｑ，２Ｈ）， １．５０（ｓ，９Ｈ）， １．２０（ｔ，３Ｈ）。

Compound 5 (100.82 g, 0.33 mol, 1.0 equivalent), Compound 7 (101.05 g, 0.44 mol, 1.30 equivalent), and cesium carbonate (177.12 g, 0.54 mol, 1.60 equivalent) ) Was suspended in DMSO (250 mL, 2.5 vol) and stirred vigorously at 55-60 ° C. for 48 h (reaction completion was determined by HPLC). The mixture is cooled to 20-30 ° C., the base is maintained with the internal temperature of the reaction mixture below 30 ° C., and 1N HCl (water) solution (540 mL, 1.60 eq) is carefully and slowly added. And quenched. Upon cooling, a precipitate formed which was filtered and washed with water (2 × 250 mL, 2 × 2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated to reflux again and maintained at reflux for 30 minutes, at which point the suspension was cooled to 10 ° C. The resulting solid is then filtered and washed with water (2 × 250 mL, 2 × 2.5 volumes) followed by absolute ethanol (250 mL, 2.5 volumes) and then into a vacuum oven. And dried at 50-60 ° C. The title compound 8 was obtained as a white crystalline solid. ( ¹ H NMR, 500 MHz; CDCl ₃ ) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (T, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H).

  (Example 4: Preparation of 2- (2,4-difluorophenyl) -6- (2,6-difluorophenylamino) nicotinic acid (9))

化合物８（１００ｇ，０．２０４ｍｏｌ，１．００当量）に、５０℃未満の温度で維持しながら濃硫酸（２８５ｍＬ，２．８５容積，５．２４ｍｏｌ）を蒸留水（４６５ｍＬ，４．６５容積）にゆっくりと添加することによって調製した７Ｍ硫酸溶液を添加した。上記混合物を、上記反応が完了するまで、１００±５℃へと加熱した。次いで、上記混合物を３０±５℃へと冷却し、さらなる水（７５０ｍＬ，７．５ｖｏｌ）を添加した。次いで、酢酸イソプロピル（２Ｌ，２０容積）を添加し、上記混合物を１５分間にわたって攪拌した。攪拌を止め、その相を分離させた。その水相を分離し、水（７．５容積）を、その油相に充填した。上記混合物を１５分間にわたって攪拌し、研磨濾過し（ｐｏｌｉｓｈ ｆｉｌｔｅｒｅｄ）、次いで、上記水相を排出した。上記有機層の合計容積を、４５±５℃において真空蒸留法によって４容積へと減らした。得られたスラリーを、−１０℃へと１２時間にわたって冷却し、濾過した。上記フィルターおよびケーキを、冷酢酸イソプロピル（３容積）で洗浄し、上記固体を、５０±５℃において真空下で乾燥させて、標題化合物９を白色固体として得た。（^１Ｈ ＮＭＲ，５００ＭＨｚ； ＤＭＳＯ−ｄ_６） δ １２．５０（ｓ，１Ｈ）， ９．２５（ｓ，１Ｈ）， ８．０７（ｄ，１Ｈ）， ７．３９（ｑ，１Ｈ）， ７．２９（ｍ，１Ｈ）， ７．１８（ｍ，３Ｈ）， ７．０９（ｍ，１Ｈ）， ６．２５（ｍ，１Ｈ）。

Concentrated sulfuric acid (285 mL, 2.85 volumes, 5.24 mol) was added to compound 8 (100 g, 0.204 mol, 1.00 equiv) at a temperature below 50 ° C. with distilled water (465 mL, 4.65 volumes). A 7M sulfuric acid solution prepared by slowly adding to was added. The mixture was heated to 100 ± 5 ° C. until the reaction was complete. The mixture was then cooled to 30 ± 5 ° C. and additional water (750 mL, 7.5 vol) was added. Then isopropyl acetate (2 L, 20 vol) was added and the mixture was stirred for 15 min. Agitation was stopped and the phases were allowed to separate. The aqueous phase was separated and water (7.5 volumes) was charged to the oil phase. The mixture was stirred for 15 minutes, polish filtered and then the aqueous phase was drained. The total volume of the organic layer was reduced to 4 volumes by vacuum distillation at 45 ± 5 ° C. The resulting slurry was cooled to −10 ° C. over 12 hours and filtered. The filter and cake were washed with cold isopropyl acetate (3 volumes) and the solid was dried under vacuum at 50 ± 5 ° C. to give the title compound 9 as a white solid. ( ¹ H NMR, 500 MHz; DMSO-d ₆ ) δ 12.50 (s, 1H), 9.25 (s, 1H), 8.07 (d, 1H), 7.39 (q, 1H), 7 .29 (m, 1H), 7.18 (m, 3H), 7.09 (m, 1H), 6.25 (m, 1H).

  Example 5: Preparation of 2- (2,4-difluorophenyl) -6- (1- (2,6-difluorophenyl) ureido) nicotinamide (10)

トリホスゲン（３８．８７ｇ，０．１２７６ｍｏｌ，０．９当量）および化合物９（５１．１４ｇ，０．１４１２ｍｏｌ，１当量）を、反応器に充填した。次いで、無水ＴＨＦ（４８６ｍＬ，９．５容積）を添加し、その透明な溶液を、−３０±５℃へと冷却した。ＴＨＦ（１０３ｍＬ，２．５容積）中のジイソプロピルエチルアミン（７３．７９ｍＬ，０．４２４ｍｏｌ，３．０当量）を、その温度を−２０℃より低く維持して、上記反応器に添加した。添加後、上記反応混合物を、２０±３℃へと加温した。上記混合物を２時間にわたって攪拌し、次いで、セライト（登録商標）を通して濾過し、そのケーキを、ＴＨＦ（７６７ｍＬ，１５容積）ですすいだ。その濾液を−３０℃へと冷却し、無水ＮＨ_３（３当量）を添加した。その得られた白色スラリーを、Ｎ_２でパージし、２０±３℃へと１時間にわたって加温した。次いで、上記反応混合物を、０±５℃へと３０分間にわたって冷却した。上記混合物を再び濾過し、上記反応器を、ＴＨＦ（２５５ｍＬ，５容積）ですすいだ。上記ケーキを、Ｈ_２Ｏ（２５５ｍＬ，５．０容積）ですすぎ、続いて、１Ｎ Ｈ_２ＳＯ_４（１０容積）ですすいだ。次いで、上記固体を真空オーブンへと移し、３５±３℃で乾燥させて、標題化合物１０を白色固体として得た。（^１Ｈ ＮＭＲ，５００ＭＨｚ； ＤＭＳＯ−ｄ_６） δ ７．９７（ｄ，１Ｈ）， ７．８５（ｓ，１Ｈ）， ７．５６（ｑｕｉｎ，１Ｈ）， ７．４５（ｑ，１Ｈ）， ７．４０（ｓ，２Ｈ）， ７．２８（ｔ，３Ｈ）， ７．１５（ｔｄ，１Ｈ）， ７．０６（ｄ，１Ｈ）。

Triphosgene (38.87 g, 0.1276 mol, 0.9 eq) and compound 9 (51.14 g, 0.1412 mol, 1 eq) were charged to the reactor. Anhydrous THF (486 mL, 9.5 vol) was then added and the clear solution was cooled to −30 ± 5 ° C. Diisopropylethylamine (73.79 mL, 0.424 mol, 3.0 eq) in THF (103 mL, 2.5 vol) was added to the reactor while maintaining the temperature below −20 ° C. After the addition, the reaction mixture was warmed to 20 ± 3 ° C. The mixture was stirred for 2 hours, then filtered through Celite® and the cake was rinsed with THF (767 mL, 15 volumes). The filtrate was cooled to −30 ° C. and anhydrous NH ₃ (3 eq) was added. The resulting white slurry was purged with N ₂ and warmed to 20 ± 3 ° C. over 1 hour. The reaction mixture was then cooled to 0 ± 5 ° C. over 30 minutes. The mixture was filtered again and the reactor was rinsed with THF (255 mL, 5 volumes). The cake was rinsed with H ₂ O (255 mL, 5.0 volumes) followed by 1N H ₂ SO ₄ (10 volumes). The solid was then transferred to a vacuum oven and dried at 35 ± 3 ° C. to give the title compound 10 as a white solid. ( ¹ H NMR, 500 MHz; DMSO-d ₆ ) δ 7.97 (d, 1H), 7.85 (s, 1H), 7.56 (quin, 1H), 7.45 (q, 1H), 7 .40 (s, 2H), 7.28 (t, 3H), 7.15 (td, 1H), 7.06 (d, 1H).

  Example 6: Preparation of 2- (2,4-difluorophenyl) -6- (1- (2,6-difluorophenyl) ureido) nicotinamide (10) in solid form

メタノール（６．５２Ｌ，１６．０容積）中の化合物１０（４０７．７４ｍＬ，１．０１ｍｏｌ，１．００当量）のスラリーを、溶液が得られるまで、６０℃へと加熱した。次いで、上記反応器の内容物を、４８℃へと冷却し、この温度で、結晶化が始まるまで維持し、３０分間にわたって攪拌し、次いで、０℃へと冷却した。上記スラリーを濾過し、上記反応器およびフィルターケーキを、予め０〜５℃に冷却したメタノール（８１６ｍＬ，２容積）ですすいだ。上記濾過ケーキを真空下で３０分間にわたって乾燥させた。次いで、上記固体を、上記反応器へと戻し、１：３ メタノール：水混合物（４．１Ｌ，１０容積）で２２℃において２４時間にわたって攪拌した。メタノール（２．０５Ｌ，５容積）を上記反応器に添加したところ、１：１ メタノール：水混合物を生じた。次いで、この溶液をさらに２４時間にわたって攪拌し、その後、上記混合物を濾過し、上記ケーキを、 水（８１８Ｌ，２容積）ですすいだ。上記固体を、真空オーブンへと移し、３８℃で乾燥させて、化合物１０を白色固体として得た。

A slurry of compound 10 (407.74 mL, 1.01 mol, 1.00 equiv) in methanol (6.52 L, 16.0 vol) was heated to 60 ° C. until a solution was obtained. The reactor contents were then cooled to 48 ° C., maintained at this temperature until crystallization began, stirred for 30 minutes, and then cooled to 0 ° C. The slurry was filtered and the reactor and filter cake were rinsed with methanol (816 mL, 2 volumes) previously cooled to 0-5 ° C. The filter cake was dried under vacuum for 30 minutes. The solid was then returned to the reactor and stirred with a 1: 3 methanol: water mixture (4.1 L, 10 volumes) at 22 ° C. for 24 hours. Methanol (2.05 L, 5 volumes) was added to the reactor, resulting in a 1: 1 methanol: water mixture. The solution was then stirred for an additional 24 hours, after which the mixture was filtered and the cake rinsed with water (818 L, 2 volumes). The solid was transferred to a vacuum oven and dried at 38 ° C. to give compound 10 as a white solid.

  Example 7: Alternative route to 2- (2,4-difluorophenyl) -6- (2,6-difluorophenylamino) nicotinic acid (9)

（工程Ａ：鹸化）
２５０ｍＬ 丸底フラスコに、化合物５およびＴＨＦを室温で充填した。次いで、１Ｍ ＬｉＯＨ溶液をフラスコに添加した。得られた混合物を約４０℃へと約３時間にわたって加熱し、次いで、室温へと冷却し、約２日間攪拌した。上記反応系を、ＨＰＬＣによってモニターし得る。撹拌後、上記混合物を、分離漏斗へと移し、１００ｍＬ ＤＣＭを添加し、上記混合物を、１００ｍＬ 水で洗浄した。その有機層を分離し、水相を、１１０ｍＬ １Ｎ ＨＣｌ水溶液で中和し、ＤＣＭ（３×１００ｍＬ）で抽出した。上記有機層を合わせ、濃縮して、化合物１１を白色固体として得た。Ｈ ＮＭＲ（５００．０ＭＨｚ，ＤＭＳＯ） １３．５（ｂｓ，ＯＨ） ｄ ８．３１（ｄ，Ｊ＝８．３Ｈｚ，Ｈ）， ７．７０（ｄ，Ｊ＝８．２Ｈｚ，Ｈ）， ７．６２（ｄｄ，Ｊ＝８．６，１５．２Ｈｚ，Ｈ）， ７．３５−７．３１（ｍ，Ｈ）， ７．２１（ｔｄ，Ｊ＝８．５，３．６Ｈｚ，Ｈ）， ３．３３（ｓ，Ｈ）， ２．５１（ｄ，Ｊ＝１．７Ｈｚ，Ｈ） ｐｐｍ。

(Process A: Saponification)
A 250 mL round bottom flask was charged with compound 5 and THF at room temperature. A 1M LiOH solution was then added to the flask. The resulting mixture was heated to about 40 ° C. for about 3 hours, then cooled to room temperature and stirred for about 2 days. The reaction system can be monitored by HPLC. After stirring, the mixture was transferred to a separatory funnel, 100 mL DCM was added and the mixture was washed with 100 mL water. The organic layer was separated and the aqueous phase was neutralized with 110 mL 1N aqueous HCl and extracted with DCM (3 × 100 mL). The organic layers were combined and concentrated to give compound 11 as a white solid. H NMR (500.0 MHz, DMSO) 13.5 (bs, OH) d 8.31 (d, J = 8.3 Hz, H), 7.70 (d, J = 8.2 Hz, H), 7. 62 (dd, J = 8.6, 15.2 Hz, H), 7.35-7.31 (m, H), 7.21 (td, J = 8.5, 3.6 Hz, H), 3 .33 (s, H), 2.51 (d, J = 1.7 Hz, H) ppm.

(Process B: Coupling)
A 100 mL round bottom flask was charged with Compound 20 (1.0015 g, 3.714 mmol) in MBTE (10 mL), followed by addition of Compound 6 (600 μL, 5.572 mmol). The resulting mixture was cooled to an internal temperature of −8 ° C. to −10 ° C. with an ice / acetone bath, followed by potassium bis (trimethylsilyl) amide (while maintaining the temperature of the mixture below about −5 ° C. A 1M solution of 9.3 mL, 9.300 mmol) was added dropwise (over 1 hour). After the addition of the base, the reaction mixture was quenched with 20 mL 1M HCl at room temperature. The mixture was washed with 20 mL water and 50 mL ethyl acetate. The aqueous phase was washed with ethyl acetate at least once more. The organic layer was concentrated followed by the addition of DCM (25 mL). The resulting solid was suspended, filtered and washed with 50 mL DCM. When the solid was analyzed, the presence of Compound 9 was confirmed.

  In other embodiments, the base used in the coupling step can also be selected from LiHMDS (55 ° C.), NaHMDS (55 ° C.), KOtBu, and nBuLi.

  Example 8: Alternative route to 2- (2,4-difluorophenyl) -6- (1- (2,6-difluorophenyl) ureido) nicotinamide (10)

いくつかの実施形態において、化合物１０を、ＣＤＩ、ＴＨＦ、ＮＨ_４ＯＨもしくはトルエン／メチルクロロホルメート／ＮＥｔ_３／ＮＨ_４ＯＨを使用して、アミド化合物１２の段階的形成によって生成し得る。化合物１０は、化合物１５を、ＣＨ_３ＣＮ、ＤＭＳＯ、ＭｅＴＨＦ、ＴＨＦ、ＤＭＦ、もしくはＤＭＳＯのような溶媒の存在下で、クロロスルホニルイソシアネートで処理することによって、その後に形成され得る。

In some embodiments, compound 10 may be generated by stepwise formation of amide compound 12 using CDI, THF, NH ₄ OH or toluene / methyl chloroformate / NEt ₃ / NH ₄ OH. Compound 10 can be subsequently formed by treating compound 15 with chlorosulfonyl isocyanate in the presence of a solvent such as CH ₃ CN, DMSO, MeTHF, THF, DMF, or DMSO.

(Other embodiments)
All publications and patents mentioned in this disclosure are herein incorporated to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Incorporated as a reference. In the event that the meaning of a term in any of the above patents or publications incorporated by reference conflicts with the meaning of a term used in this disclosure, the meaning of the term in this disclosure is intended to prevail. Moreover, the foregoing discussion merely discloses and describes exemplary embodiments of the present invention. Those skilled in the art will recognize from this discussion and from the accompanying drawings and claims that various changes, modifications and variations depart from the spirit and scope of the invention as defined in the following claims. It is easy to recognize what can be done there.

For example, the present invention provides:
(Item 1)
Compound of formula 4:

A process for preparing a compound of formula 2:

And a compound of formula 3:

And in the presence of a polar aprotic solvent, wherein
  Each R ₁ , R ₂ , R ₄ And R ₅ Is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R ', CO ₂ N (R ') ₂ , NR’CO ₂ R ', NR'C (O) NR' ₂ , OC (O) NR ' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ Independently selected from R ', OC (O) R';
  Each R 'is hydrogen, C _1-6 Independently selected from aliphatic or 5-6 membered carbocyclic or heterocyclic ring systems optionally substituted with 1 to 3 substituents, wherein the substituents are halo, C _1-6 Alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 Selected independently from the aliphatic;
  Each R ₃ Is hydrogen, C _1-6 Selected from aliphatic and aryl, wherein the aryl is C _1-6 Aliphatic, aryl, nitro, CN, CO ₂ R ', CO ₂ N (R ') ₂ , OR ’, NCO ₂ R ', NR'C (O) N (R') ₂ Or OC (O) N (R ′) ₂ Optionally substituted with;
  Each X is independently a leaving group; and
  Each Z is C _1-6 Aliphatic, benzyl, Fmoc, or -SO ₂ Selected independently from R ',
process.
(Item 2)
The solvent is DMSO, NMP, CH ₃ The process according to item 1, comprising CN or DMF.
(Item 3)
The process of item 2, wherein the solvent comprises DMSO.
(Item 4)
4. The process according to any one of items 1 to 3, wherein the step of coupling the compound of formula 2 and the compound of formula 3 is performed in the presence of a base.
(Item 5)
Item 5. The process according to Item 4, wherein the base is a metal carbonate or a metal phosphate.
(Item 6)
Item 6. The process according to Item 5, wherein the base is a metal carbonate.
(Item 7)
Item 5. The process according to Item 4, wherein the base is cesium carbonate or potassium carbonate.
(Item 8)
Item 8. The process according to Item 7, wherein the base is cesium carbonate.
(Item 9)
Item 5. The process of item 4, wherein the base is a metal phosphate.
(Item 10)
Item 10. The process according to Item 9, wherein the base is potassium phosphate.
(Item 11)
Item 11. The process according to any of Items 1-10, wherein the step of coupling the compound of Formula 2 with the compound of Formula 3 is performed in a temperature range of about 55-75 ° C.
(Item 12)
Compound of formula 5:

A process for preparing
Compound of formula 4:

For hydrolysis using protonic acid
Where
  Each R ₁ , R ₂ , R ₄ And R ₅ Is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R ', CO ₂ N (R ') ₂ , NR’CO ₂ R ', NR'C (O) NR' ₂ , OC (O) NR ' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ Independently selected from R, OC (O) R ';
  Each R 'is hydrogen, C _1-6 Independently selected from aliphatic or 5-6 membered carbocyclic or heterocyclic ring systems optionally substituted with 1 to 3 substituents, wherein the substituents are halo, C _1-6 Alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 Selected independently from the aliphatic;
  Each R ₃ Is hydrogen, C _1-6 Selected from aliphatic and aryl, wherein the aryl is C _1-6 Aliphatic, aryl, nitro, CN, CO ₂ R ', CO ₂ N (R ') ₂ , OR ’, NCO ₂ R ', NR'C (O) N (R') ₂ Or OC (O) N (R ′) ₂ Optionally substituted with;
  Each Z is C _1-6 Aliphatic, benzyl, Fmoc, or -SO ₂ Selected independently from R ',
process.
(Item 13)
Item 13. The process according to Item 12, wherein the hydrolysis of the compound of Formula 4 is performed in the presence of a solvent.
(Item 14)
14. A process according to item 13, wherein the solvent is water.
(Item 15)
The protonic acid is H ₂ SO ₄ , HCl or H ₃ PO ₄ The process according to any of items 12 to 14, wherein
(Item 16)
The protonic acid is H ₂ SO ₄ The process according to item 15, wherein
(Item 17)
The process of item 16, wherein the final concentration of sulfuric acid is about 7M.
(Item 18)
18. Process according to any of items 12-17, wherein the hydrolysis of the compound of formula 4 is carried out in a temperature range of about 60-105 ° C.
(Item 19)
19. A process according to any of items 12-18, wherein the hydrolysis is performed using a one pot reaction.
(Item 20)
Compound of formula 1:

A process for preparing
  Compound of formula 5:

The following:
    i) a urea-forming reagent;
    ii) an amidation reagent; and
    iii) anhydrous ammonia
Performing amidation and urea formation on the compound of formula 5 by treating with
Where
  Each R ₁ , R ₂ , R ₄ And R ₅ Is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R ', CO ₂ N (R ') ₂ , NR’CO ₂ R ', NR'C (O) NR' ₂ , OC (O) NR ' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ Independently selected from R ', OC (O) R'; and
  Each R 'is hydrogen, C _1-6 Independently selected from aliphatic or 5-6 membered carbocyclic or heterocyclic ring systems optionally substituted with 1 to 3 substituents, wherein the substituents are halo, C _1-6 Alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 Selected independently from aliphatic,
process.
(Item 21)
21. A process according to item 20, wherein the amidation reagent urea formation is phosgene, triphosgene or diphosgene.
(Item 22)
Item 22. The process according to Item 21, wherein the urea-forming reagent is phosgene, triphosgene or diphosgene.
(Item 23)
23. A process according to any of items 20-22, wherein the amidation reagent and urea-forming reagent are added simultaneously.
(Item 24)
24. A process according to any of items 20-23, wherein the amidation reagent and the urea-forming reagent are the same.
(Item 25)
25. A process according to any of items 20 to 24, wherein the amidation and urea formation performed on the compound of formula 5 is performed in the presence of a base.
(Item 26)
26. A process according to item 25, wherein the base is a Hunig base, triethylamine or diisopropylethylamine.
(Item 27)
27. A process according to item 26, wherein the base is diisopropylethylamine.
(Item 28)
28. A process according to any of items 20 to 27, wherein the amidation and urea formation performed on the compound of formula 5 is performed in the presence of a solvent.
(Item 29)
29. A process according to item 28, wherein the solvent is THF, MeTHF, or toluene.
(Item 30)
30. A process according to item 29, wherein the solvent is THF.
(Item 31)
31. A process according to any of items 20-30, wherein the compound of formula 5 is treated with anhydrous ammonia after treatment with the amidation / urea forming reagent.
(Item 32)
32. The process of item 31, wherein anhydrous ammonia is added to the product obtained after treatment of the compound of formula 5 with the amidation / urea forming reagent without isolation of the product.
(Item 33)
Item 21. The method further comprising isolating the solid material after treating the solution with anhydrous ammonia and washing the solid material with water followed by an acid wash to obtain a compound of Formula 1. process.
(Item 34)
The acid wash is 1N H ₂ SO ₄ 34. The process according to item 33, comprising washing the solid material according to
(Item 35)
A process for providing a stable solid form of a compound of formula 1, wherein the process comprises:

Comprising slurrying a solid form of
  Each R ₁ , R ₂ , R ₄ And R ₅ Is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R ', CO ₂ N (R ') ₂ , NR’CO ₂ R ', NR'C (O) NR' ₂ , OC (O) NR ' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ Independently selected from R ', OC (O) R'; and
  Each R 'is hydrogen, C _1-6 Independently selected from aliphatic or 5-6 membered carbocyclic or heterocyclic ring systems optionally substituted with 1 to 3 substituents, wherein the substituents are halo, C _1-6 Alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 Selected independently from aliphatic,
process.
(Item 36)
36. The process of item 35, wherein the compound of Formula 1 is stirred in a homogeneous or heterogeneous solvent system.
(Item 37)
38. The process of item 36, wherein the solvent system comprises methanol and water.
(Item 38)
38. The process of item 37, wherein the methanol: water ratio in the solvent system is about 1: 3.
(Item 39)
38. The process of item 36, wherein the methanol: water ratio in the solvent system is about 1: 1.
(Item 40)
40. The process of items 35-39, wherein the compound is agitated for at least about 20 hours.
(Item 41)
The compound is stirred in a solvent system having a methanol: water ratio of about 1: 3 for at least about 20 hours, and then in a solvent system having a methanol: water ratio of about 1: 1 for at least about 20 hours. 41. The process of item 40, wherein the process is agitated.
(Item 42)
Each R ₁ , R ₂ , R ₄ And R ₅ 42. The process according to any of items 1-41, wherein is independently selected from hydrogen, F, Cl, Br, I, OTs or OMs.
(Item 43)
Each R ₁ , R ₂ , R ₄ And R ₅ 43. The process according to item 42, wherein is independently selected from hydrogen or F.
(Item 44)
Each R ₃ Is hydrogen or C _1-6 20. A process according to any of items 1-19, selected independently from aliphatic.
(Item 45)
Each R ₃ 45. The process according to item 44, wherein is independently selected from hydrogen or ethyl.
(Item 46)
Each Z is independently C _1-6 The process according to any of items 1 to 19, which is aliphatic.
(Item 47)
47. A process according to item 46, wherein each Z is independently tert-butyl.
(Item 48)
Compound of formula 5:

A process for preparing
  Compound of formula 13:

Against
Including the step of carrying out hydrolysis using a protic acid, wherein
  Each R ₁ , R ₂ , R ₄ And R ₅ Is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R ', CO ₂ N (R ') ₂ , NR’CO ₂ R ', NR'C (O) NR' ₂ , OC (O) NR ' ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ Independently selected from R ', OC (O) R';
  Each R 'is hydrogen, C _1-6 Independently selected from aliphatic or 5-6 membered carbocyclic or heterocyclic ring systems optionally substituted with 1 to 3 substituents, wherein the substituents are halo, C _1-6 Alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 Selected independently from the aliphatic; and
  Each R ₃ Is hydrogen, C _1-6 Selected from aliphatic and aryl, wherein the aryl is C _1-6 Aliphatic, aryl, nitro, CN, CO ₂ R ', CO ₂ N (R ') ₂ , OR ’, NCO ₂ R ', NR'C (O) N (R') ₂ Or OC (O) N (R ′) ₂ Is replaced as needed,
process.
(Item 49)
49. A process according to item 48, wherein the hydrolysis of the compound of formula 5 is carried out in the presence of a solvent.
(Item 50)
50. A process according to item 49, wherein the solvent is water.
(Item 51)
51. A process according to any of items 48 to 50, wherein the protonic acid is sulfuric acid.
(Item 52)
52. The process of any of items 48-51, wherein the final concentration of sulfuric acid is about 7M.
(Item 53)
Compound 10:

A process for preparing
  Compound 11:

And compound 6:

Was dissolved in methyl tert-butyl ether (MTBE), the mixture was treated with a base, and the mixture was stirred at a temperature of about −8 ° C. to −10 ° C. to couple compound 11 and compound 6 Compound 9:

Obtaining
  Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran;
  Stirring the solution until the reaction is complete; and
  Treating the solution with anhydrous ammonia;
Including the process.
(Item 54)
54. A process according to item 53, wherein the base is LiHMDS, NaHMDS, KHMDS, KOtBu, or nBuLi.
(Item 55)
55. A process according to item 54, wherein the base is KHMDS.
(Item 56)
56. The process of item 55, wherein the reaction temperature is between about −20 ° C. and 25 ° C.
(Item 57)
57. The process of item 56, wherein the reaction temperature is between about −10 ° C. and −8 ° C.
(Item 58)
54. The process of item 53, further comprising isolating the solid material after treating the solution with anhydrous ammonia and washing the solid material with water followed by an acid wash to obtain the compound 10. .
(Item 59)
The acid wash is 1N H ₂ SO ₄ 59. The process according to item 58, comprising washing the solid material according to
(Item 60)
Compound 10:

A process for preparing
  Compound 5:

And compound 7:

Is dissolved in dimethyl sulfoxide, the mixture is treated with cesium carbonate, and the mixture is coupled at a temperature of about 50-65 ° C. to couple compound 5 and compound 7 to give compound 8:

Obtaining
  Compound 8 is treated with about 7M aqueous sulfuric acid and the mixture is stirred at a temperature of about 95-105 ° C. to give compound 9:

Obtaining
  Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran;
  Stirring the solution until the reaction is complete; and
  Treating the solution with anhydrous ammonia
Including the process.
(Item 61)
Stirring compound 10 in a solvent system comprising methanol and water, wherein the methanol: water ratio is about 1: 3 over at least about 20 hours; adding methanol to the mixture 63. The process of item 60, further comprising: changing the solvent ratio to about 1: 1 with methanol: water; and continuing to stir for at least about 20 hours.
(Item 62)
61. The process of item 60, further comprising isolating the solid material after treating the solution with anhydrous ammonia and washing the solid material with water followed by an acid wash to obtain the compound 10. .
(Item 63)
The acid wash is 1N H ₂ SO ₄ 63. The process according to item 62, comprising washing the solid material according to.
(Item 64)
64. A compound produced by the process of any of items 1-63.
(Item 65)
64. A pharmaceutical composition comprising a compound produced by the process of any of items 1-63.

Claims (65)

Compound of formula 4:

A process for preparing a compound of formula 2:

And a compound of formula 3:

And in the presence of a polar aprotic solvent, wherein each R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, Nitro, CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR′CO ₂ R ′, NR′C (O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Independently selected from Br, I, OTs, OMs, OSO ₂ R ′, OC (O) R ′;
Each R ′ is independently of hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with 1 to 3 substituents. Selected and the substituent is independently selected from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic;
Each R ₃ is selected from hydrogen, C _1-6 aliphatic, and aryl, wherein the aryl is C _1-6 aliphatic, aryl, nitro, CN, CO ₂ R ′, CO ₂ N (R ′) ₂ , Optionally substituted with OR ′, NCO ₂ R ′, NR′C (O) N (R ′) ₂ , or OC (O) N (R ′) ₂ ;
Each X is independently a leaving group; and each Z is independently selected from C _1-6 aliphatic, benzyl, Fmoc, or —SO ₂ R ′.
process. The process of claim 1, wherein the solvent comprises DMSO, NMP, CH ₃ CN, or DMF. The process of claim 2, wherein the solvent comprises DMSO. The process according to any one of claims 1 to 3, wherein the step of coupling the compound of formula 2 and the compound of formula 3 is performed in the presence of a base. The process of claim 4, wherein the base is a metal carbonate or a metal phosphate. The process of claim 5, wherein the base is a metal carbonate. The process of claim 4, wherein the base is cesium carbonate or potassium carbonate. The process of claim 7, wherein the base is cesium carbonate. The process of claim 4, wherein the base is a metal phosphate. The process of claim 9, wherein the base is potassium phosphate. 11. The process according to any of claims 1 to 10, wherein the step of coupling the compound of formula 2 and the compound of formula 3 is performed in a temperature range of about 55 to 75 ° C. Compound of formula 5:

A process for preparing
Compound of formula 4:

Wherein R ₁ , R ₂ , R ₄ and R ₅ are each hydrogen, aliphatic, optionally substituted aryl, nitro , CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR′CO ₂ R ′, NR′C (O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Br , I, OTs, OMs, OSO ₂ R, OC (O) R ′;
Each R ′ is independently of hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with 1 to 3 substituents. Selected and the substituent is independently selected from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic;
Each R ₃ is selected from hydrogen, C _1-6 aliphatic, and aryl, wherein the aryl is C _1-6 aliphatic, aryl, nitro, CN, CO ₂ R ′, CO ₂ N (R ′) ₂ , Optionally substituted with OR ′, NCO ₂ R ′, NR′C (O) N (R ′) ₂ , or OC (O) N (R ′) ₂ ;
Each Z is independently selected from C _1-6 aliphatic, benzyl, Fmoc, or —SO ₂ R ′;
process. The process according to claim 12, wherein the hydrolysis of the compound of formula 4 is carried out in the presence of a solvent. The process of claim 13, wherein the solvent is water. The protonic _acid, H ₂ SO _{4, HCl,} or a _H 3 PO _4, A process according to any one of claims 12 to 14. The process of claim 15, wherein the protic acid is H ₂ SO ₄ . The process of claim 16, wherein the final concentration of sulfuric acid is about 7M. The process according to any of claims 12 to 17, wherein the hydrolysis of the compound of formula 4 is carried out in the temperature range of about 60-105C. The process according to any of claims 12 to 18, wherein the hydrolysis is carried out using a one-pot reaction. Compound of formula 1:

A process for preparing
Compound of formula 5:

The following:
i) a urea-forming reagent;
ii) amidation reagent; and iii) subjecting the compound of formula 5 to amidation and urea formation by treatment with anhydrous ammonia, wherein each R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR′CO ₂ R ′, NR′C ( O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Br, I, OTs, OMs, OSO ₂ R ′, OC (O) R ′; and each R ′ is Independently selected from hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with 1 to 3 substituents; Groups are halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic Selected independently from the
process. 21. The process of claim 20, wherein the amidating reagent urea formation is phosgene, triphosgene or diphosgene. The process of claim 21, wherein the urea-forming reagent is phosgene, triphosgene or diphosgene. 23. A process according to any of claims 20-22, wherein the amidation reagent and urea-forming reagent are added simultaneously. 24. A process according to any of claims 20 to 23, wherein the amidation reagent and urea-forming reagent are the same. 25. A process according to any of claims 20 to 24, wherein the amidation and urea formation performed on the compound of formula 5 is performed in the presence of a base. 26. The process of claim 25, wherein the base is a Hunig base, triethylamine or diisopropylethylamine. 27. The process of claim 26, wherein the base is diisopropylethylamine. 28. A process according to any of claims 20 to 27, wherein the amidation and urea formation performed on the compound of formula 5 is performed in the presence of a solvent. 30. The process of claim 28, wherein the solvent is THF, MeTHF, or toluene. 30. The process of claim 29, wherein the solvent is THF. 31. A process according to any of claims 20-30, wherein the compound of formula 5 is treated with anhydrous ammonia after treatment with the amidation / urea forming reagent. 32. The process of claim 31, wherein anhydrous ammonia is added to the product obtained after treatment of the compound of formula 5 with the amidation / urea forming reagent without isolation of the product. 21. The method of claim 20, further comprising isolating the solid material after treating the solution with anhydrous ammonia and washing the solid material with water followed by an acid wash to obtain a compound of Formula 1. Process. The acid wash, a wash of the solid material by _1N H 2 SO _4, The process of claim 33. A process for providing a stable solid form of a compound of formula 1, wherein the process comprises:

Each of R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ′, CO ₂ R ′, CO ₂ N (R ′) ₂ , NR′CO ₂ R ′, NR′C (O) NR ′ ₂ , OC (O) NR ′ ₂ , F, Cl, Br, I, OTs, OMs, Independently selected from OSO ₂ R ′, OC (O) R ′; and each R ′ is optionally substituted with hydrogen, C _1-6 aliphatic, or 1-3 substituents. Independently selected from a 6-membered carbocyclic or heterocyclic ring system, wherein the substituent is from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic Independently selected,
process. 36. The process of claim 35, wherein the compound of Formula 1 is stirred in a homogeneous or heterogeneous solvent system. 40. The process of claim 36, wherein the solvent system comprises methanol and water. 38. The process of claim 37, wherein the methanol: water ratio in the solvent system is about 1: 3. 37. The process of claim 36, wherein the methanol: water ratio in the solvent system is about 1: 1. 40. The process of claims 35-39, wherein the compound is stirred for at least about 20 hours. The compound is stirred in a solvent system having a methanol: water ratio of about 1: 3 for at least about 20 hours and then in a solvent system having a methanol: water ratio of about 1: 1 for at least about 20 hours. 41. The process of claim 40, wherein the process is agitated. Each _{R 1,} R 2, _{R 4} and _{R 5} are hydrogen, F, Cl, Br, I, are independently selected from OTs or OMs, The process according to any of claims 1-41. Each _{R 1,} R 2, _{R 4} and _{R 5} are independently selected from hydrogen or F, the process according to claim 42. Each _{R 3} is independently selected from hydrogen or _{C 1-6} aliphatic, A process according to any one of claims 1 to 19. Each R ₃ is independently selected from hydrogen or ethyl, A process according to claim 44. 20. A process according to any of claims 1 to 19, wherein each Z is independently _C1-6 aliphatic. 48. The process of claim 46, wherein each Z is independently tert-butyl. Compound of formula 5:

A process for preparing
Compound of formula 13:

Against
Including hydrolysis using a protic acid, wherein each R ₁ , R ₂ , R ₄ and R ₅ is hydrogen, aliphatic, optionally substituted aryl, nitro, CN, OR ', CO ₂ R', CO ₂ N (R ') ₂ , NR'CO ₂ R', NR'C (O) NR ' ₂ , OC (O) NR' ₂ , F, Cl, Br, I, OTs , OMs, OSO ₂ R ′, OC (O) R ′;
Each R ′ is independently of hydrogen, C _1-6 aliphatic, or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with 1 to 3 substituents. And the substituent is independently selected from halo, C _1-6 alkoxy, cyano, nitro, amino, hydroxy, and C _1-6 aliphatic; and each R ₃ is hydrogen, C _1-6 aliphatic And aryl selected from C _1-6 aliphatic, aryl, nitro, CN, CO ₂ R ′, CO ₂ N (R ′) ₂ , OR ′, NCO ₂ R ′, NR′C ( Optionally substituted with O) N (R ′) ₂ , or OC (O) N (R ′) ₂ ,
process. 49. The process of claim 48, wherein the hydrolysis of the compound of formula 5 is performed in the presence of a solvent. 50. The process of claim 49, wherein the solvent is water. 51. A process according to any of claims 48 to 50, wherein the protic acid is sulfuric acid. 52. The process of any of claims 48-51, wherein the final concentration of sulfuric acid is about 7M. Compound 10:

A process for preparing
Compound 11:

And compound 6:

Was dissolved in methyl tert-butyl ether (MTBE), the mixture was treated with a base, and the mixture was stirred at a temperature of about −8 ° C. to −10 ° C. to couple compound 11 and compound 6 Compound 9:

Obtaining
Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran;
Stirring the solution until the reaction is complete; and treating the solution with anhydrous ammonia;
Including the process. 54. The process of claim 53, wherein the base is LiHMDS, NaHMDS, KHMDS, KOtBu, or nBuLi. 55. The process of claim 54, wherein the base is KHMDS. 56. The process of claim 55, wherein the reaction temperature is between about -20C and 25C. 57. The process of claim 56, wherein the reaction temperature is between about −10 ° C. and −8 ° C. 54. The method of claim 53, further comprising isolating the solid material after treating the solution with anhydrous ammonia, and washing the solid material with water followed by an acid wash to obtain the compound 10. process. The acid wash, a wash of the solid material by _1N H 2 SO _4, The process of claim 58. Compound 10:

A process for preparing
Compound 5:

And compound 7:

Is dissolved in dimethyl sulfoxide, the mixture is treated with cesium carbonate, and the mixture is coupled at a temperature of about 50-65 ° C. to couple compound 5 and compound 7 to give compound 8:

Obtaining
Compound 8 is treated with about 7M aqueous sulfuric acid and the mixture is stirred at a temperature of about 95-105 ° C. to give compound 9:

Obtaining
Treating compound 9 with triphosgene and diisopropylethylamine in the presence of tetrahydrofuran;
Stirring the solution until the reaction is complete; and treating the solution with anhydrous ammonia. Stirring compound 10 in a solvent system comprising methanol and water, wherein the methanol: water ratio is about 1: 3 over at least about 20 hours; adding methanol to the mixture 61. The process of claim 60, further comprising: changing the solvent ratio to about 1: 1 with methanol: water; and continuing to stir for at least about 20 hours. 61. The method of claim 60, further comprising isolating the solid material after treating the solution with anhydrous ammonia, and washing the solid material with water followed by an acid wash to obtain the compound 10. process. The acid wash, a wash of the solid material by _1N H 2 SO _4, The process of claim 62. 64. A compound produced by the process of any of claims 1-63. 64. A pharmaceutical composition comprising a compound produced by the process of any of claims 1-63.